Selective serotonin reuptake inhibitors (commonly abbreviated as SSRIs) are a class of pharmaceutical antidepressant medications. They are commonly prescribed for the treatment of major depressive disorders. Other conditions include anxiety disorders, obsessive-compulsive disorder, migraine, attention-deficit hyperactivity disorder (ADHD), addiction/dependence, and sleep disorders. The exact pharmacological mechanism of action SSRIs is unknown.[1] They are believed to increase the extracellular level of the neurotransmitterserotonin, eventually leading to improved mood.[citation needed][clarification needed]

SSRIs can be dangerous when used in combination with other substances that increase or modulate serotonin such as MDMA and Monoamine Oxidase Inhibitors (MAOIs). A combination with these substances can lead to serotonin syndrome and potentially be fatal. SSRIs do not work for everyone and take 3-6 weeks to start having noticeable effects.[2]

Mechanism of action

SSRIs are believed to increase the extracellular level of the neurotransmitterserotonin by limiting its reuptake into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporters. Pure SSRIs show only weak affinities for the noradrenaline and dopamine transporters.

SSRIs also lead to an increased level of cAMP (cyclic adenosine monophosphate), brain-derived neurotrophic factor, and several other regulatory neuromodulators. Different SSRIs have different binding profiles, which may lead to different effects.[3]

Subjective effects

Physical effects

SedationorStimulation - Most SSRIs are sedating while others can be mildly stimulating. The sedation produced by SSRIs is usually very mild during the day, but very intense at night. This can make one unable to stay awake at night, however is usually considered a positive effect by most people, as depression often is accompanied by insomnia.

Orgasm suppression - This effect is usually is mild and only delays orgasms, however in some people, particularly older users, SSRIs can make one completely unable to reach orgasm. This is usually treated by either switching to a different antidepressant, or adding a DNRI such as bupropion.

Nausea - Nausea is mild and is usually only present upon first introduction and usually subsides after 6-8 weeks.

Headaches - Headaches are usually only present upon first introduction and usually subside after 6-8 weeks.

Paradoxical effects

Suicidal ideation[4] - Upon first introduction, some users (especially people under the age of 25)[5] can experience increase suicidal and self harming thoughts and behaviors. This effect usually subsides within 6-8 weeks.

Experience reports

Examples

Citalopram

Citalopram is an SSRI sold under the brand name Celexa in the United States. Citalopram is indicated for the treatment of a major depressive disorder. Citalopram was approved in 1998 by the Food and Drug Administration for the treatment of major depressive disorder.[6] Citalopram is almost exclusively found as the hydrobromide salt, which is the only form approved by the FDA.[7]

Escitalopram

Escitalopram is an SSRI sold under the brand name Lexapro in the United States. Escitalopram is indicated for the treatment of major depressive disorder and anxiety disorders. It is the s-enantiomer of citalopram, and both have similar efficacy. Escitalopram was FDA approved in 2002.[8]

Fluoxetine

Fluoxetine is an SSRI commonly sold under the brand name Prozac. Fluoxetine is indicated for the treatment of major depressive disorder, bulimia nervosa, obsessive-compulsive disorder, panic disorder, and premenstrual dysphoric disorder. Fluoxetine is sometimes used in conjunction with olanzapine (an atypical antipsychotic) to treat bipolar I disorder as well as treatment-resistant depression.[9]A single pill medication called Symbyax is a combination of olanzapine and fluoxetine.[10]Fluoxetine is on the World Health Organization's list of essential medicines, a list of medicines needed for a basic and effective health system.[11]Fluoxetine was first FDA approved in 1987.

Fluvoxamine

Fluvoxamine is an SSRI that is used to treat obsessive-compulsive disorder. Fluvoxamine was first approved by the FDA in 1994.[12]Fluvoxamine has the greatest affinity for the σ1 (sigma-1) receptor, where it acts as an agonist, which may contribute to its biological effects.[13]

Paroxetine

Paroxetine is an SSRI that is sold under the brand name Paxil. Paroxetine is used to treat major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder, anxiety disorders, premenstrual dysphoric disorder, and under the brand name Brisdelle, it is used to treat hot flashes related to menopause. Paroxetine was first approved by the FDA in 1992.[14]

Sertraline

Sertraline is an SSRI that is sold under the brand name Zoloft. Sertraline is used to treat major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder, anxiety disorders, panic disorder, and premenstrual dysphoric disorder. Sertraline was first FDA approved in 1991.[15]Unlike most SSRIs, sertraline, has somewhat significant activity at the dopamine transporter protein[16] and could be considered a serotonin-dopamine reuptake inhibitor.

Other SSRIs

Several other SSRIs have been developed and marketed. Dapoxetine is used in some countries to treat premature ejaculation. Indalpine and zimelidine were originally marketed but later withdrawn due to the emergence of Guillain–Barré syndrome, a serious neurological disease. Cericlamine and panuramine were developed but never marketed.[citation needed]

Drug interactions

A wide array of substances is contraindicated with SSRIs. Substances that increase extracellular serotonin may increase the risk of serotonin syndrome, particularly substances like MDMA, dextromethorphan, tramadol and pethidine. Independent research should be done before taking any substances while on an SSRI to ensure there is no drug interaction. Some dietary supplements such as 5-HTP and St. John's Wort can lead to serotonin syndrome if taken by someone currently medicated with an SSRI.

Some NSAID analgesics may increase the risk of excess bleeding in those who take SSRIs. NSAIDs include ibuprofen, aspirin (acetylsalicylic acid), and naproxen.

Most SSRIs inhibit the function of certain cytochrome P450 enzymes that metabolize other substances so that SSRIs may lead to an increased or decreased serum level of certain medications.

Combinations

Psychedelics - Due do the downregulation of 5-HT2A receptors caused by SSRIs, psychedelics can have a reduced effect. SSRIs can also reduce the chance of having a bad trip due to its anxiolytic effects.

Cannabis - While on SSRIs, the anxiety and paranoia experienced on cannabis may be less intense, or not experienced at all.

Dangerous interactions

Dextromethorphan - Dextromethorphan is a serotonin releaser as well as an SSRI, therefore has a potential to cause serotonin syndrome, a potentially deadly condition caused by extremely high serotonin levels. Although serotonin syndrome caused by this combination is uncommon, it is strongly advised not to combine them, especially if either is at a high dose.

Other antidepresants - Combining SSRIs with other antidepressants such as tricyclic antidepressants and MAOIs can result in serotonin syndrome. Non serotonergic antidepressants such as bupropion are not dangerous to combine with SSRIs.